Cart is empty 
Over the last few decades, severely obese people and their doctors so often faced the same clinical dilemma. Try to manage the condition through a combination of lifestyle changes and medications — often without getting anywhere close to a healthy weight — or bet on life-altering bariatric surgery.
Wouldn’t it be amazing if patients struggling with severe obesity no longer had to settle for a “compromise therapy?”
Retatrutide is still in extensive phase 3 trials, but this investigational peptide has already made waves. It’s changed what’s scientifically possible with medications alone. Phase 2 trials show an average weight loss of 24.2 percent at 48 weeks. For the first time ever, an experimental peptide can get the same kinds of results as a sleeve gastrectomy.
Even more exciting? Retatrutide doesn’t hit plateaus. Participants’ weight loss curves were still going strong at 48 weeks — meaning Retatrutide strongly seems to have a higher therapeutic ceiling than Semaglutide and Tirzepatide.
Retatrutide attacks obesity from all sides. It’s a triple agonist that targets GLP-1, GIP, and glucagon — so that it can soothe hunger, manage blood sugar levels, and burn fat at record rates. Three angles. One goal. Make bariatric surgery obsolete.
A Very Brief History of Retatrutide
Anyone who’s been following weight loss peptides already has a good idea of how it started.
First, there were incretin-based peptides that activated the GLP-1 receptor to manage blood sugar levels and appetite — Liraglutide and Semaglutide, super effective for moderate weight loss, but not quite powerful enough for everyone.
Then came dual GLP-1 and GIP agonist peptides. Tirzepatide blew researchers away with its undeniably powerful results. But why stick with a “twincretin” when you can target three receptors at once?
The Eli Lilly researchers who developed Retatrutide wanted to see what a third one could do — and they picked the glucagon receptor as their target for a very specific reason. GLP-1 and GIP could work together to tame chronically overactive appetites and improve metabolic markers. And the third addition, that would zoom in on the glucagon receptor? That, they hoped, could send energy burning into overdrive and burn fat super effectively.
We could say that the rest is history, but not quite. Phase 2 trials have shown results so impressive that “wow” doesn’t begin to cover it. The TRIUMPH phase 3 trial is currently ongoing, with participants in 169 locations spread over multiple countries. [1] At the same time, other studies continue to puzzle out what’s possible with Retatrutide. It’s the most successful experimental peptide for truly massive weight loss already, but it’s also still at the very beginning of its clinical journey. No wonder scientists are so excited about Retatrutide!
How Retatrutide Works
This is worth drilling down on, because some peptides do one thing pretty well. Retatrutide is a “three for the price of one” compound with triple action.
It does what the natural gut hormone GLP-1 does, just like Semaglutide — Retatrutide boosts insulin when blood sugar levels get too high and keeps glucagon down. It works to keep people feeling full for longer in two different ways, by getting the stomach to empty itself out less quickly and by switching the appetite center in the brain to “I’m full” mode.
Retatrutide also does what Tirzepatide does — work the GIP receptor to make insulin respond to glucose more effectively than GLP-1 peptides would on their own.
Then, there’s the third bit. The glucagon component makes patients burn more calories at rest, so they lose weight even faster (and, very importantly, without doing any extra exercise to make it happen).
The Most Important Findings in Retatrutide Studies So Far & Its Observed Effects
The milestone phase 2 trial published in the New England Journal of Medicine proved that Retatrutide wasn’t just a clever theory — it’s a very promising new treatment that attacks obesity from multiple different angles and improves metabolic health significantly. You’ve already seen the TL; DR version, but Retatrutide research gets a whole lot more interesting.
Superb Weight Loss – That Previously Seemed Impossible
So… the 24.2 percent weight loss “benchmark” was, of course, the main headline after that phase 2 trial. Just in case that number still sounds a little too abstract, that’s very nearly a quarter of participants’ starting body weights — or 58 lbs/26 kg in real terms.
For the record, weight loss results after bariatric surgery usually cap out at 25 to 30 percent. Bariatric surgery has helped countless people manage severe obesity, so we’re not here to disparage it — but it also comes with the risk of malnutrition, depression, ulcers, and “dumping syndrome” on top of the risks always associated with major abdominal surgery. [2] Achieving comparable weight loss with Retatrutide isn’t only more convenient, but also safer.
On top of that, there’s the “missing plateau.” Participants in the highest-dose group weren’t plateauing out. This study didn’t yet show the full power of Retatrutide.
Retatrutide Also Delivers a Metabolic Reset
Getting to a healthy weight is the first goal of obesity management, but it’s neither where treatment ends nor where Retatrutide stops being useful.
Studies saw prediabetic participants on Retatrutide return to normal, non-diabetic blood glucose and HbA1c levels — so Retatrutide has the potential to prevent type 2 diabetes. [3] Besides that, blood pressure improved and triglycerides and LDL cholesterol went down. [4] “Weight loss peptide” doesn’t begin to do Retatrutide justice. It’s a metabolic health manager.
How Retatrutide Impacts Non-Alcoholic Fatty Liver Disease
NAFLD is a shockingly common complication of overweight and obesity. (We mean it; most major medical associations routinely estimate that it affects a full quarter, if not more, of the global population.) There’s no approved treatment — one of the main reasons Retatrutide brings such hope.
MRI-PDFF imaging done after 48 weeks of Retatrutide showed something very exciting. The vast majority of non-diabetic participants who had non-alcoholic fatty liver disease going into the trial no longer met the diagnostic criteria by the end. No medication before Retatrutide had that same result. [5]
Since no treatment currently exists, that’s pushed Retatrutide to the top of the list of potential treatment candidates for metabolic dysfunction-associated steatotic hepatitis — the most dangerous stage of NAFLD.
Safety, Side Effects, and the Road Still Ahead
The road from development to first proof of concept and on to clinical use is always long — but given its success, Retatrutide has moved through these stages quite quickly.
The human trials conducted so far have demonstrated that Retatrutide has manageable side effects of exactly the kind seen with GLP-1 peptides. The most common ones are temporary nausea, diarrhea, and constipation. Not all participants have them. For those who do, they don’t necessarily experience all and they usually wear off after a while. [6, 7]
Retatrutide has now entered the phase 3 clinical trial stage — the TRIUMPH program. That series of studies is designed to do several things. First, TRIUMPH should replicate the success of Retatrutide on a much larger scale. Then, it needs to confirm that most patients tolerate Retatrutide very well.
From there, the path to clinical use is wide open — and the many patients awaiting a new anti-obesity or non-alcoholic fatty liver disease treatment can look forward to good news. In the meantime, research might very well branch off into new directions. So often, it turns out that a peptide has novel, previously hidden effects that would benefit entirely different patient groups.
Retatrutide is undeniably one of the most exciting compounds being studied right now and we, for one, can’t wait to see what the next big headline says.
How Is Retatrutide Delivered?
All clinical trials done to date have relied on one route of administration — designed to be patient-friendly, with the possibility of self-administration. That is, Retatrutide is delivered via one convenient weekly subcutaneous or intramuscular injection.
That wasn’t an accident. Retatrutide was designed to be long-acting from the start. That lowers the (otherwise very real) risk that patients won’t want to stick with it because of annoyingly frequent injections that could also cause some skin irritation. The same model proved very successful for other weight loss peptides, like Semaglutide and Tirzepatide, and it also makes researching Retatrutide much more convenient.
Researchers have to reconstitute lyophilized Retatrutide with bacteriostatic water to get to a precise concentration, but if (or rather, more likely, when) it’s approved for clinical use, patients prescribed Retatrutide will almost certainly get a pre-filled, ready-to-use injector pen.
What is The Current Calculated Dosing Protocols for Retatrutide Done by Scientists?
The famous phase 2 trial continues to be an important source of information for researchers — among other reasons because it established a very clear dosing protocol designed to make Retatrutide as effective as possible while simultaneously lowering the risk of side effects.
As always, this section isn’t there to provide medical or research design advice — just to get you up to date on research protocols.
The trial delivered Retatrutide once a week via subQ or IM injection, with a dose escalation schedule that gives patients time to adjust:
- A 1 mg dose in weeks one through four
- Double that dose, 2 mg, in weeks five to eight
- Up to 6 mg in weeks nine to 12
- From week 13 going forward, a 10-12 mg maintenance dose every week
The trial identified 12 mg as the most effective maintenance dose. It’s what led to the 24+ percent weight reductions you’ve already read about. The effects of Retatrutide are very dependent on the dose used, so future research that tests the compound with lower doses for more moderate weight loss is possible.
Experimental research and biohacker spaces are other sources of interesting data. There, dosing is often lower — but gradual escalation is still the norm. You might read about starting doses between 0.5 and 1 mg in the first four weeks, for example, which then go up in the same way or more incrementally, in 1 to 2 mg steps. The final dose may be as low as 4 mg or as high as 8 mg, but rarely 12 mg. Actual study durations are often 12 to 16 weeks.
These more conservative doses are interesting for researchers studying less drastic weight loss or, potentially, also non-alcoholic fatty liver disease. Slow escalation allows researchers to study how the model responds — so that the protocol can be stopped or adjusted if side effects prove sufficiently uncomfortable. It also, again, tries to minimize the odds of gastrointestinal symptoms, which study participants sometimes report in the period after they join a trial.
FAQs
The answer to that question depends on the research goal at hand to a very large extent. The data show that Retatrutide is significantly more effective at inducing weight loss — Retatrutide leads to an average weight loss of 24.2 percent after 48 weeks (with no slowdown!), and Semaglutide usually plateaus at 16 percent.
Retatrutide goes the extra mile because it acts on three hormones. It’s GLP-1 + GIP + glucagon. Semaglutide targets just GLP-1. Besides keeping appetites in check, Retatrutide also burns fat for energy. That’s one of the things that makes it more effective.
The TRIUMPH phase 3 trial is in full swing, and it actually shouldn’t be much longer before FDA approval becomes an option. Research, meanwhile, always continues.
One aspect of its mechanism of action is inducing a fast-like state, so Retatrutide tells the liver to make energy from stored fat. That same process can boost ketone bodies. The studies published so far didn’t explicitly look for ketosis, and that’s not the main purpose of Retatrutide, but based on its mechanism of action, Retatrutide does lead to a similar state as following a ketogenic diet.
Yes, the participants got dietary counseling and were invited to adopt healthier diets. That’s standard in weight loss research, and it doesn’t negate the impressive results seen with Retatrutide. Obesity causes metabolic and neurological changes that make it very hard to stick to a diet. Retatrutide reduces appetite and cravings. It makes sticking to a diet plan easier. Although it slashes appetite effectively even without a diet plan, the quality of the calories participants get matters for general health. The importance of a healthy diet shouldn’t be overlooked.
Scientific References and Sources
- https://clinicaltrials.gov/study/NCT05882045[↩]
- https://my.clevelandclinic.org/-/scassets/files/org/bariatric/guides/risks-and-complications-of-bariatric-surgery.ashx?la=en[↩]
- https://www.researchsquare.com/article/rs-7103001/v1[↩]
- https://pmc.ncbi.nlm.nih.gov/articles/PMC12326405/[↩]
- https://www.nature.com/articles/s41591-024-03018-2[↩]
- https://www.degruyterbrill.com/document/doi/10.1515/jbcpp-2025-0113/html[↩]
- https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.70209[↩]